Direct Mannich‐Type Reactions Promoted by Frustrated Lewis Acid/Brønsted Base Catalysts

Abstract

Direct Mannich-type reactions that afford both α- and β-amino esters by the reaction of a broad range of carbonyl compounds and aldimines are disclosed. The transformation is promoted by a sterically frustrated Lewis acid/Brønsted base pair, which is proposed to operate cooperatively: Within the catalyst complex, an enolate is generated that then reacts with a hydrogen-bond-activated imine. Noncovalent interactions between reactants and the catalyst provide selectivity and new opportunities for future catalyst design.

Catalytic Direct‐Type Addition Reactions of Alkylarenes with Imines and Alkenes

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Catalytic addition reactions of very weakly acidic nonactivated alkylarenes such as toluene and its derivatives were developed by using astrongly basic mixed catalyst system under mild reaction conditions.T he addition reactions with imines and alkenes proceeded smoothly under proton-transfer conditions to affordthe desired products in good to high yields, and high levels of regio-and stereoselectivity were achieved. [2] Although an umber of carbon pronucleophiles have been successfully employed in the reactions,asignificant limitation has been the range of available substrate structures;t hat is, carbon pronucleophiles bearing weakly acidic hydrogen atoms (pK a > 30 in DMSO) are difficult to employ, [3] and more than one equivalent of strong base is typically required to promote the desired reactions.Onthe other hand, we have recently reported asimple but powerful method that extends the use of these Brønsted base catalyzed reactions of weakly acidic pronucleophiles.T hrough designing strongly basic reaction intermediates,t ermed product bases,c atalytic stereoselective addition reactions of simple amides, [4a] esters, [4b,c] alkylazaarenes, [4d] and others [4e,f] have proceeded smoothly. [1] Among them, Brønsted base catalyzed C À Cb ond-forming reactions are promising because the reactions proceed under proton-transfer conditions with ideal atom economy.

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“…[1] Among them, Brønsted base catalyzed C À Cb ond-forming reactions are promising because the reactions proceed under proton-transfer conditions with ideal atom economy. [2] Although an umber of carbon pronucleophiles have been successfully employed in the reactions,asignificant limitation has been the range of available substrate structures;t hat is, carbon pronucleophiles bearing weakly acidic hydrogen atoms (pK a > 30 in DMSO) are difficult to employ, [3] and more than one equivalent of strong base is typically required to promote the desired reactions.Onthe other hand, we have recently reported asimple but powerful method that extends the use of these Brønsted base catalyzed reactions of weakly acidic pronucleophiles.T hrough designing strongly basic reaction intermediates,t ermed product bases,c atalytic stereoselective addition reactions of simple amides, [4a] esters, [4b,c] alkylazaarenes, [4d] and others [4e,f] have proceeded smoothly. However,m uch more weakly acidic carbon pronucleophiles (pK a > 40 in DMSO) such as simple alkylarenes remain very challenging substrates to activate by using typical Brønsted base catalyst systems.Nonactivated alkylarenes such as toluene,e thylbenzene, and xylenes are commercially available,i nexpensive,a nd easy-to-handle reagents;i ndeed, they are commonly used as solvents in organic synthesis because of their high stability.…”

Boron‐Based Catalysts for C−C Bond‐Formation Reactions

“…In 2016, Wasa and co‐workers described a direct Mannich‐type reaction from carbonyl compounds 47 (ketones, amides, and esters) and aldimines 48 , by employing a catalytic amount of 1 in combination with the bulky base 1,2,2,6,6‐pentamethylpiperidine (PMP) (Scheme ) . It was proposed that boron enolate was generated as a key intermediate during the reaction; this subsequently reacted with aldimines 48 to afford Mannich‐type products 49 .…”

Direct Mannich‐Type Reactions Promoted by Frustrated Lewis Acid/Brønsted Base Catalysts

“…[23] Keywords: acid-base catalysis ·boron ·frustrated Lewis pairs · Lewis acids ·Mannich-type reactions We are thankful to Professors Amir H. Hoveyda, T. Ross Kelly,J ames P. Morken (Boston College), and Mr. Richard Y. Liu (MIT) for helpful discussions,aswell as to Dr. Bo Li and Malte S. Mikus (Boston College) for X-ray crystallographic analysis.…”

“…We are thankful to Professors Amir H. Hoveyda, T. Ross Kelly,J ames P. Morken (Boston College), and Mr. Richard Y. Liu (MIT) for helpful discussions,aswell as to Dr. Bo Li and Malte S. Mikus (Boston College) for X-ray crystallographic analysis. [23] Keywords: acid-base catalysis ·boron ·frustrated Lewis pairs · Lewis acids ·Mannich-type reactions…”